Alzheimer's disease (AD) is the most common form of dementia (loss of memory) in the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. Recent evidence has revealed that elevated beta amyloid levels in brain not only precede tau pathology but also correlate with cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent studies have shown that aggregated beta amyloid is toxic to neurons in cell culture and has a detrimental effect on memory. This suggests that reducing beta amyloid levels is a viable therapeutic strategy for the treatment of AD.
Beta amyloid protein is composed mainly of 39-42 amino acid peptides and is produced from a larger precursor protein called amyloid precursor protein (APP) by the sequential action of the proteases beta and gamma secretase. Although rare, cases of early onset AD have been attributed to genetic mutations in APP that lead to an overproduction of either total beta amyloid protein or its more aggregation-prone 42 amino acid isoform. Furthermore, people with Down's Syndrome possess an extra chromosome that contains the gene that encodes APP and thus have elevated beta amyloid levels and invariably develop AD later in life.
One approach to the inhibition of beta amyloid production is to target the recently described beta secretase enzyme. Three groups have recently reported peptide-based beta secretase inhibitors. A second approach is to target gamma secretase the other enzyme involved in beta amyloid production. Although gamma secretase has not yet been fully characterized, recent evidence suggests that the presenilins may be gamma secretases. Several gamma secretase inhibitors have been designed based upon the amino acid sequence of the APP cleavage site. Importantly, a gamma secretase inhibitor DAPT (LY374973, AN37124) has been recently shown to reduce beta amyloid protein levels in mice brains in vivo after oral administration.
What are needed are compounds that are effective in lowering beta amyloid production.